Apolipoprotein E ε4 Polymorphism as a Risk Factor for Ischemic Stroke: A Systematic Review and Meta-Analysis

Introduction. Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS. Methods. To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations. Results. A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene epsilon 4 mutation and IS was confirmed (epsilon 4 vs. epsilon 3 allele: pooled OR=1.374, 95% CI, 1.214-1.556; epsilon 2/epsilon 4 vs. epsilon 3/epsilon 3: pooled OR=1.233, 95% CI, 1.056-1.440; epsilon 3/epsilon 4 vs. epsilon 3/epsilon 3: pooled OR=1.340, 95% CI, 1.165-1.542; epsilon 4/epsilon 4 vs. epsilon 3/epsilon 3: pooled OR=1.833, 95% CI, 1.542-2.179; and APOE epsilon 4 carriers vs. non-epsilon 4 carriers: pooled OR=1.377; 95% CI, 1.203-1.576). Interestingly, APOE epsilon 4 mutation showed a dose-response correlation with IS risk (epsilon 4/epsilon 4 vs. epsilon 2/epsilon 4: pooled OR=1.625; 95% CI, 1.281-2.060; epsilon 4/epsilon 4 vs. epsilon 3/epsilon 4: pooled OR=1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis. Conclusions. These observations reveal that specific APOE epsilon 4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE epsilon 4 mutation was related to SAD subtype onset without a cumulative effect.

Automated summary

This meta-analysis confirmed the association between APOE gene epsilon 4 mutation and ischemic stroke, showing a dose-response correlation in the risk of IS. Additionally, similar conclusions were drawn in the small artery disease subtype.